Platelet-Derived Growth Factor (PDGF) is a protein that controls cell growth and division within the body. It functions as a signaling molecule, instructing cells to proliferate, migrate, and differentiate, processes fundamental for maintaining healthy tissues. PDGF influences both normal physiological activities and the development of certain diseases.
The Basics of PDGF
PDGF exists in different forms, or isoforms: PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, and PDGF-DD. Each isoform binds to specific cell surface receptors: Platelet-Derived Growth Factor Receptor-alpha (PDGFR-α) and Platelet-Derived Growth Factor Receptor-beta (PDGFR-β).
These receptors are transmembrane glycoproteins with tyrosine kinase activity, primarily found on mesenchymal cells like fibroblasts, pericytes, and smooth muscle cells. When a PDGF isoform binds to its corresponding receptor, it causes the receptor to dimerize, forming homodimers (PDGFR-αα, PDGFR-ββ) or heterodimers (PDGFR-αβ). This dimerization activates the receptor’s internal tyrosine kinase, triggering intracellular signaling pathways that regulate cell proliferation, migration, and survival. PDGF is primarily produced by platelets, but other cells like macrophages, vascular smooth muscle cells, and endothelial cells also synthesize and secrete it.
PDGF’s Crucial Roles in the Body
PDGF plays an important role in the body’s natural healing and repair mechanisms. When an injury occurs, PDGF is released, attracting cells like fibroblasts and monocytes-macrophages to the wound site, essential for tissue repair. This promotes the proliferation and migration of these cells, accelerating the formation of extracellular matrix and collagen, reducing healing time. Studies indicate that PDGF can increase the healing rate of chronic wounds by up to 30%.
PDGF is also involved in the formation and maintenance of blood vessels, processes like angiogenesis and vasculogenesis. PDGF-BB, for instance, recruits pericytes and vascular smooth muscle cells to newly formed endothelial tubes, contributing to vessel maturation and stability.
PDGF also contributes to embryonic development, influencing the growth and differentiation of various tissues and organs. PDGFR-α signaling is necessary for interstitial cell proliferation in the embryonic testis and kidney, and for mesenchymal proliferation in the early stages of intestine, skin, and lung development. PDGF-C is also involved in the development of the neural tube and neural crest cells.
When PDGF Goes Awry
Dysregulation of PDGF signaling contributes to various pathological conditions. In cancer, overexpression of PDGF or its receptors can lead to uncontrolled cell growth, tumor formation, and metastasis. PDGF can promote tumor growth by stimulating angiogenesis, the formation of new blood vessels that supply tumors, and by directly promoting cancer cell proliferation and migration. This has been observed in various cancers, including glioblastoma, sarcomas, and breast cancer.
PDGF also plays a role in fibrotic diseases, characterized by excessive scar tissue formation. In conditions such as pulmonary fibrosis, liver cirrhosis, and kidney fibrosis, PDGF drives the proliferation of fibroblasts and the deposition of extracellular matrix, leading to tissue hardening and organ dysfunction. Increased expression of PDGFR-α and PDGFR-β on myofibroblasts amplifies the fibrotic response to PDGF.
PDGF contributes to the development of atherosclerosis, where plaque builds up inside arteries. PDGF’s mitogenic properties stimulate the proliferation and migration of vascular smooth muscle cells, which accumulate within forming lesions, contributing to plaque expansion. Elevated levels of PDGF have been found in atherosclerotic lesions, with macrophages and smooth muscle cells serving as sources of PDGF in these plaques.
Harnessing PDGF for Medical Treatments
Understanding PDGF’s role in various biological processes has opened avenues for medical treatments. Recombinant human PDGF (rhPDGF), specifically PDGF-BB, is used therapeutically to promote healing in chronic wounds, such as diabetic foot ulcers. This application leverages PDGF’s ability to stimulate cellular migration, proliferation, and subsequent matrix formation, accelerating the wound healing process. The U.S. Food and Drug Administration (FDA) has approved rhPDGF for the repair of periodontal defects.
In addition to direct therapeutic uses, PDGF signaling pathways are targets for drug development, particularly in cancer and fibrotic conditions. Drugs that inhibit PDGFR tyrosine kinase activity, such as imatinib and sunitinib, are used to block aberrant PDGF signaling that drives uncontrolled cell growth and proliferation in certain cancers. These inhibitors can reduce tumor growth and metastasis by targeting PDGFRs on cancer cells, vascular cells, and stromal cells within the tumor microenvironment. For fibrotic diseases, targeting PDGFR-β has shown promise in reducing fibrotic progression, as seen with drugs like nintedanib for idiopathic pulmonary fibrosis.